The overall goal of this 5 year research plan is to elucidate the molecular mechanism responsible for the modulation of T cell function and interleukin-2 (IL-2) deregulation by the structurally-related endocannabinoids, anandamide (AEA) and 2-arachidonyl glycerol (2-AG). Presently, the teleological role of the endocannabinoid system is unknown but there is a growing body of evidence suggesting that it may significantly contribute to the maintenance of immunologic homeostasis. Numerous studies have demonstrated profound effects on biological systems by AEA and 2-AG, with the immune system representing one of the most extensively characterized. The significance of the current proposed studies is that they will provide direct mechanistic insight into the molecular mechanism by which endocannabinoids modulate T cell function, specifically IL-2 regulation. Novel preliminary results are presented demonstrating that IL-2 suppression by both AEA and 2-AG are dependent on COX-2 metabolism leading to the activation of the nuclear receptor, peroxisome proliferator activated receptor gamma (PPARgamma), independently of CB1 and CB2. Additional results are present suggesting that the specific mechanism involves the disruption of the nuclear factor of activated T cells (NFAT) by PPARgamma activation. Based on the observations described above and other preliminary data presented in the proposal, our present investigation will test the hypothesis: Suppression of IL-2 by the endocannabinoids, AEA and 2-AG, is mediated through disruption of NFAT regulation by two distinct cannabinoid receptor-independent mechanisms: (a) altered intracellular calcium regulation; and (b) activation of PPARgamma following COX-2-mediated conversion of AEA and 2-AG into PPARgamma agonists. We will test our hypothesis using the following specific aims (SA): SA1 is to characterize the role altered intracellular calcium regulation by AEA and 2-AG plays in deregulation of NFAT and, consequently, suppression of IL-2 gene expression; SA2 is to characterize the role of COX-2 on the deregulation of NFAT and suppression of IL-2 by AEA and 2-AG; SA3 is to characterize the role of PPARgamma activation by AEA and 2-AG treatment in altered NFAT regulation and suppression of IL-2; and SA4 is to identify and characterize the bioactive forms of AEA and 2-AG responsible for PPARgamma activation and to elucidate its contribution to IL- 2 suppression.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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NeuroAIDS and other End-Organ Diseases Study Section (NAED)
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Sharp, Charles
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Michigan State University
Schools of Medicine
East Lansing
United States
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Pires, Paulo W; Girgla, Saavia S; McClain, Jonathon L et al. (2013) Improvement in middle cerebral artery structure and endothelial function in stroke-prone spontaneously hypertensive rats after macrophage depletion. Microcirculation 20:650-61
Karmaus, Peer W F; Chen, Weimin; Crawford, Robert et al. (2013) ?9-tetrahydrocannabinol impairs the inflammatory response to influenza infection: role of antigen-presenting cells and the cannabinoid receptors 1 and 2. Toxicol Sci 131:419-33
Raman, Priyadarshini; Kaplan, Barbara L F; Kaminski, Norbert E (2012) 15-Deoxy-ýýýýýý,ýýýýý-prostaglandin Jýýý-glycerol, a putative metabolite of 2-arachidonyl glycerol and a peroxisome proliferator-activated receptor ýý ligand, modulates nuclear factor of activated T cells. J Pharmacol Exp Ther 342:816-26
Chen, Weimin; Kaplan, Barbara L F; Pike, Schuyler T et al. (2012) Magnitude of stimulation dictates the cannabinoid-mediated differential T cell response to HIVgp120. J Leukoc Biol 92:1093-102
Karmaus, Peer W F; Chen, Weimin; Crawford, Robert B et al. (2011) Deletion of cannabinoid receptors 1 and 2 exacerbates APC function to increase inflammation and cellular immunity during influenza infection. J Leukoc Biol 90:983-95
Moussaieff, Arieh; Rimmerman, Neta; Bregman, Tatiana et al. (2008) Incensole acetate, an incense component, elicits psychoactivity by activating TRPV3 channels in the brain. FASEB J 22:3024-34
Hu, S Shu-Jung; Bradshaw, H B; Chen, J S-C et al. (2008) Prostaglandin E2 glycerol ester, an endogenous COX-2 metabolite of 2-arachidonoylglycerol, induces hyperalgesia and modulates NFkappaB activity. Br J Pharmacol 153:1538-49
Rimmerman, N; Hughes, H V; Bradshaw, H B et al. (2008) Compartmentalization of endocannabinoids into lipid rafts in a dorsal root ganglion cell line. Br J Pharmacol 153:380-9
O'Dell, David K; Rimmerman, Neta; Pickens, Sarah R et al. (2007) Fatty acyl amides of endogenous tetrahydroisoquinolines are active at the recombinant human TRPV1 receptor. Bioorg Med Chem 15:6164-9
Tan, Bo; Bradshaw, Heather B; Rimmerman, Neta et al. (2006) Targeted lipidomics: discovery of new fatty acyl amides. AAPS J 8:E461-5

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